Composition for the treatment of fistula

ABSTRACT

A composition for use in the treatment of fistula, the composition comprising activated carbon.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a U.S. National Phase application under 35 U.S.C. §371 ofInternational Patent Application No. PCT/EP2012/069513, filed Oct. 3,2012, which published as WO2013/050404, and which claims the priority ofEuropean Patent Application No. 11183665.6 filed on Oct. 3, 2011 andBritish Patent Application No. 1117148.5 filed on Oct. 3, 2011. Theforegoing applications and WO2013/050404 are hereby incorporated byreference in their entirety.

The invention relates to a pharmaceutical composition comprisingactivated carbon particles for the treatment of fistula, for examplerectal or anal fistula.

BACKGROUND

A fistula is an abnormal conduit or connection between bodily organs orvessels that do not usually connect. Fistulas or fistulae can form inmany parts of the body. Anal fistula and rectal fistula are conditionsin which tubes form between a sufferer's rectum and intestines, or otherinternal organs, or between a sufferer's rectum and the external skinadjacent to the sufferer's anus. For example, fistulas situated high inthe anus (high anal fistula) may connect with the urinary tract, andfistulas situated low in the anus (low anal fistula) may, in women, passinto the vagina. In addition to significant pain, rectal and analfistulas commonly become infected and accumulate pus. Furthermore, suchfistulas can allow the leakage of fecal matter from the rectum.

Anal and rectal fistulas may form as a result of disease or infection.For example, anal fistulas may arise if a sufferer's anal glands becomeblocked, thereby forming an abscess that points through from the rectumto the skin surface in the anal region. The growth of fistulas may beaccelerated, and fistulas themselves may be maintained, by a local buildup of substances which cause irritation (e.g. in the rectum).

Anal and rectal fistulas may be treated by surgical procedures. Suchprocedures are undesirable, however. One potential side-effect of thesurgical procedure to treat fistula is an increased probability that apatient will develop anal incontinence in the years following thesurgery. The use of glue (e.g. fibrin glue) and plug procedures reducesthe likelihood of anal incontinence, but nevertheless surgicalprocedures are generally relatively expensive compared to medication,and are generally less convenient and less preferable to the patient.

Activated carbon has been proposed for use in the treatment of rectaland anal fistulas. However, there are a number of problems associatedwith the use of activated carbon for this purpose. Activated carbon istypically supplied as an extremely fine powder having a high surfacearea. The European Pharmacopoeia describes activated carbon as a black,light powder free from grittiness. There are, however, problemsassociated with handling such a powder as the fine scale of the powderparticles means the activated carbon tends to contaminate its immediatesurroundings with a fine powder dust of activated carbon. These finepowders of activated carbon may have particles sizes predominatelysmaller than 170 mesh (predominantly smaller than 89 μm), i.e. in whichmost of the particles in the powder would pass through a sieve of meshsize 170 and in which the average particle size is considerably smallerthan this. The inventor of the present application investigated atypical sample of fine activated carbon powder using a microscope andfound that the particles were smaller than 20 μm in diameter. Such apowder is, therefore, inherently dirty and difficult to handle. A finepowder also does not flow easily, and it is difficult to administer adry dose of activated carbon. A dry dose of activated carbon is a doseof activated carbon that has been maintained in dry conditions until thepoint of delivery.

To alleviate some of the handling problems, activated carbon haspreviously been prepared for oral administration. However, orallyadministered activated carbon must pass through a patient's entiredigestive system before it reaches the rectal region and in doing so alarge (and unpredictable) proportion of the carbon will have adsorbedvarious chemicals and lost its activity, or otherwise loses itsactivity, depending on various factors such as amount of food in gut,inter patient variations and day to day variations. By increasing thedose of orally administered activated carbon it may be possible toincrease the proportion of carbon that reaches the rectum in anactivated state. However, activated carbon absorbs many essentialchemicals and nutrients on passing through the patient's digestivesystem and the long-term administration of large oral doses of activatedcarbon over a prolonged period is therefore undesirable.

Activated carbon has been prepared for rectal administration bypre-mixing to form a suspension with a liquid (e.g. propylene glycol).The problem with such suspensions is that the carbon may lose itsactivity very quickly due to adsorption of components of the liquid bythe activated carbon. For example, experiments have compared the amountof phenazone adsorbed per 100 g activated carbon suspended in eitherwater or 50% water/propylene glycol. The results showed that in water,activated carbon adsorbed 43 g phenazone per 100 g carbon; in 50%propylene activated carbon adsorbed only 16 g per 100 g phenazone.Clearly, the activity of the carbon is markedly reduced by adsorption ofthe propylene glycol. Suspensions of activated carbon, therefore, needto be used shortly after preparation and have little practicalshelf-life.

Activated carbon has also been coated or otherwise formulated to allowit to pass through a patient's digestive system when taken orally. Forexample, U.S. Pat. No. 5,554,370 discloses capsules for oraladministration of activated carbon. It may be difficult to prepare acoating that accurately dissolves to release the activated carbon onlyonce it has passed into a patient's rectum. Furthermore, such coating orencapsulation may itself reduce or eliminate the activity of the carbon(e.g. in the same manner as described above for suspensions) and therebymay reduce the effectiveness of such coated particles for the treatmentof rectal and anal fistulas.

JP2005-089306 discloses a suppository comprising activated carbon. Thesuppository is formulated with other excipients (e.g. gelatine, wax suchas Witepsol W35) which effectively coat the activated carbon. Asdiscussed above, coating reduces or eliminates the activity of thecarbon and thereby may reduce the effectiveness of such coated particlesfor the treatment of rectal and anal fistulas. Further, suppositorieswhich include activated carbon may not achieve predictable or effectiveadministration of activated carbon particles for several reasons.Firstly, administration by suppository requires effective insertion bythe patient to the required depth, which is not always achieved, and maybe unhygienic. Further, therapeutic benefit requires effective capillaryflow of activated carbon particles from the rectal cavity which may notbe achieved because of the weight of the activated carbon particlesand/or inter-patient variation of mucosal secretion; the activatedcarbon may remain at the base of the rectum and therefore not reach thesite of the fistula. Thus, suppositories including activated carbon arefar from ideal. JP2005-089306 also discloses an example of an enemaformulation. However, as indicated above, enema suspensions tend to havepoor shelf life and reduced activity due to adsorption of components ofthe liquid by the activated carbon. The inclusion of preservatives inenema suspensions of activated carbon (e.g. suspensions in water) toenhance shelf life is inappropriate because the preservative would beadsorbed by the activated carbon, thereby reducing activity of theactivated carbon and leaving the water phase unprotected.

Thus, there is a need for compositions for (use in) the treatment offistula which retain their pharmaceutical activity prior toadministration (i.e. have good shelf life), have improved handlingqualities, and are associated with predictable and repeatable dosing andgood patient compliance.

The applicants have surprisingly found that it is possible to formulateand administer activated carbon which is dust free [for exampleactivated carbon of particle size 0.02 to 1 mm, preferably of particlesize 0.05 to 1 mm (e.g in the form of “macroparticles” of particle sizefrom approximately 0.15 mm to 0.3 mm, e.g. 0.2 to 0.3 mm)], as a drypowder or dry dose. Formulation of activated carbon as a dry powderprevents deactivation of the carbon (there is no adsorption of otherexcipients or components of the administration vehicle on the activatedcarbon); allows effective administration without the problems associatedwith rectal suppositories and oral administration (particles of thissize may be administered rectally as a powder, and there is little or noloss of activity due to adsorption in the gut); and has other advantagesin terms of cleanliness and contamination (particles of this size arenot dusty).

According to the present invention there is provided a composition (e.g.a pharmaceutical composition) for use in the treatment of fistula, thecomposition comprising a dry powder (a dry dose) of activated carbonwhich is dust free. Preferably the dust free carbon is of particle size0.02 to 1 mm, preferably of particle size 0.05 to 1 mm (e.g in the formof “macroparticles” of particle size from approximately 0.15 mm to 0.3mm, e.g. 0.2 to 0.3 mm).

Thus, according to the present invention there is provided a composition(e.g. a pharmaceutical composition) for use in the treatment of fistula,the composition comprising a dry powder (a dry dose) of activated carbonof particle size 0.001 to 1 mm, for example 0.01 to 1 mm, for example0.02 to 1 mm. Preferably, the activated carbon is of particle size 0.05to 1 mm, for example 0.1 to 0.5 mm, for example 0.15 mm to 0.4 mm, forexample 0.2 to 0.3 mm. The activated carbon may be of particle size 0.15to 1 mm. Preferably the activated carbon is of average particle size0.05 to 1 mm. Preferably the activated carbon is of average particlesize 0.15 to 0.3 mm. Preferably the composition (e.g. pharmaceuticalcomposition) is for use in the treatment of rectal or anal fistula.Preferably the dry powder (dry dose) of activated carbon is free of dustor substantially free of dust.

According to the present invention in a further aspect there is provideda composition (e.g. a pharmaceutical composition) for use in thetreatment of fistula, the composition comprising a dry powder (a drydose) of activated carbon wherein 85% or more of the activated carbonparticles have diameter in the range from 0.089 mm to 0.3 mm. Theactivated carbon may be activated carbon wherein 85% or more of theactivated carbon particles have diameter in the range from 0.104 mm to0.297 mm. The activated carbon may be activated carbon wherein 85% ormore of the activated carbon particles have diameter in the range from0.125 mm to 0.297 mm. A particularly preferred activated carbon isactivated carbon wherein 85% or more of the activated carbon particleshave diameter in the range from 0.152 mm to 0.297 mm. Preferably thecomposition (e.g. pharmaceutical composition) is for use in thetreatment of rectal or anal fistula.

According to the present invention in a further aspect there is provideda dry powder (a dry dose) of activated carbon of particle size 0.001 to1 mm, for example 0.02 to 1 mm, preferably 0.05 to 1 mm (for example 0.1to 0.5 mm, for example 0.15 mm to 0.4 mm, for example 0.2 to 0.3 mm) foruse in the treatment of fistula, or for use in the manufacture of amedicament for the treatment of fistula. The activated carbon may be ofparticle size 0.05 to 1 mm. Preferably the activated carbon is ofparticle size 0.15 to 0.3 mm. The activated carbon may be of averageparticle size 0.15 to 1 mm. Preferably the fistula is rectal or analfistula. Preferably the dry powder (dry dose) of activated carbon isfree of dust or substantially free of dust.

According to the present invention in another aspect there is provided amethod of treatment of fistula comprising a step of administering (to asubject in need thereof) a pharmaceutically effective amount of acomposition comprising a dry powder (a dry dose) of activated carbon ofparticle size 0.001 to 1 mm, for example 0.02 to 1 mm, preferably 0.05to 1 mm (for example 0.1 to 0.5 mm, for example 0.15 mm to 0.4 mm, forexample 0.2 to 0.3 mm). The activated carbon may be of particle size0.15 to 1 mm. Preferably the activated carbon is of particle size 0.15to 0.3 mm. Preferably the treatment is treatment of rectal or analfistula.

According to the invention in an aspect there is provided a compositionfor use in the treatment of fistula, the composition comprising a drypowder of activated carbon of particle size 0.001 to 1 mm, for example0.02 to 1 mm, preferably 0.05 to 1 mm, wherein the composition is foradministration (to be administered) rectally as a dr y powder. Theactivated carbon may be of particle size 0.15 to 1 mm. The activatedcarbon may be of average particle size 0.15 mm to 0.3 mm.

According to the invention in an aspect there is provided a compositionfor use in the treatment of fistula, the composition comprising a drypowder of activated carbon of particle size which is dust free, whereinthe composition is for administration (to be administered) rectally as adry powder. Preferably the dust free carbon is of particle size 0.02 to1 mm, preferably of particle size 0.05 to 1 mm (e.g in the form of“macroparticles” of particle size from approximately 0.15 mm to 0.3 mm,e.g. 0.2 to 0.3 mm).

The composition (e.g. pharmaceutical composition) comprises a dry powder(dry dose) of activated carbon. Herein the terms “dry dose” and “drypowder” of activated carbon mean activated carbon that has beenmaintained in dry conditions until the point of delivery to thepatient's body. The use of a dry powder (dry dose) of activated carbonparticles means the adsorbtive capacity of the activated carbon isretained and maintained until administration.

Preferably the composition or pharmaceutical composition is for rectaladministration. The composition or pharmaceutical composition maycomprise 450 μg to 10 g activated carbon. Preferably the composition orpharmaceutical composition comprises 450 μg to 5 g activated carbon. Inan example, the composition or pharmaceutical composition comprises 450μg to 1 g activated carbon. In another example, the composition orpharmaceutical composition comprises 950 μg to 2.5 g activated carbon.In another example, the composition or pharmaceutical compositioncomprises 950 μg to 1.3 g activated carbon. In an example thecomposition or pharmaceutical composition comprises 1.2 g activatedcarbon. In an example the composition or pharmaceutical compositioncomprises 1.2 g (±10%) activated carbon. In other words, the compositionor pharmaceutical composition may comprise 1.08 to 1.32 g activatedcarbon.

The composition or pharmaceutical composition may comprise a dose (e.g.a unit dose or single dose) of 450 μg to 10 g activated carbon.Preferably the composition or pharmaceutical composition comprises adose (e.g. a unit dose or single dose) of 450 μg to 5 g activatedcarbon. In an example, the composition or pharmaceutical compositioncomprises a dose (e.g. a unit dose or single dose) of 450 μg to 1 gactivated carbon. Doses of 450 μg to 1 g activated carbon may besuitable for the treatment of children. In another example, thecomposition or pharmaceutical composition comprises a dose (e.g. a unitdose or single dose) of 950 μg to 2.5 g activated carbon. In anotherexample, the composition or pharmaceutical composition comprises a dose(e.g. a unit dose or single dose) of 950 μg to 1.3 g activated carbon.Doses of 950 μg to 2.5 g (e.g. of 950 μg to 1.3 g, e.g. doses of 1.1 g,1.2 g etc.) activated carbon may be suitable for the treatment ofadults. Preferably the composition or pharmaceutical composition is foradministration 1, 2, or 3 times a day at the dose levels above.Preferably the composition or pharmaceutical composition is foradministration after the, or each, bowel movement. The composition orpharmaceutical composition may be for treatment of rectal or analfistula in a patient with Irritable Bowel Syndrome or Crohns disease. Itwill be appreciated that dose administration to a patient with IrritableBowel Syndrome or Crohns disease may be more frequent than 1, 2, or 3times a day because bowel movements may be more frequent in suchpatients.

The activated carbon may be granular activated carbon.

Herein the term “particle size” means the width at the narrowest pointof the activated carbon particle or granule (e.g the diameter for aspherical or roughly spherical particle).

Activated carbon (e.g. granular activated carbon) and its methods ofmanufacture is well known in the art and is available from, for example,Chemviron Carbon. Preferably the activated carbon is a pharmaceutical ormedical grade activated carbon.

Activated carbon is designated by sizes such as 8×20, 20×40, or 8×30. A20×40 carbon is made of particles that will pass through a U.S. StandardMesh Size No. 20 sieve (0.84 mm) (generally specified as 85% passing)but be retained on a U.S. Standard Mesh Size No. 40 sieve (0.42 mm)(generally specified as 95% retained). A U.S. Standard Mesh Size No. 50sieve has openings of 0.297 mm; a No. 60 sieve has openings 0.251 mm; aNo. 70 sieve has openings 0.211 mm; a No. 80 sieve has openings 0.178mm; a No. 100 sieve has openings 0.152; a No. 120 sieve has openings0.125 mm, a No. 140 sieve has openings 0.104 mm, and a No. 170 sieve hasopenings 0.089 mm. A notation for indicating particle size distributionusing mesh size is to use + and − designations. A “+” before the sievemesh indicates the particles are retained by the sieve, while a “−”before the sieve mesh indicates the particles pass through the sieve.This means that typically 90% or more of the particles will have meshsizes between the two values. Thus, if the particle size of a materialis described as −80/+170 (or could also be written −80+170), then 90% ormore of the material will pass through an 80 mesh sieve and be retainedby a 170 mesh sieve. Using the figures above, it can be seen that theresulting particles will have a range of diameters between 0.089 and0.178 mm (89 and 178 micrometers). The activated carbon may be ofparticle size distribution −50/+120, wherein 90% or more of theactivated carbon particles have diameter in the range from 0.125 mm to0.297 mm. Preferably the activated carbon is of particle sizedistribution −50/+100, wherein 90% or more of the activated carbonparticles have diameter in the range from 0.152 mm to 0.297 mm.Preferably the activated carbon is of particle size distribution−50/+80, wherein 90% or more of the activated carbon particles havediameter in the range from 0.178 mm to 0.297 mm. More preferably theactivated carbon is of particle size distribution −50/+70, wherein 90%or more of the activated carbon particles have diameter in the rangefrom 0.211 mm and 0.297 mm.

The activated carbon may be an activated carbon wherein 85% or more ofthe activated carbon particles have diameter in the range from 0.089 mmto 0.3 mm. The activated carbon may be activated carbon wherein 85% ormore of the activated carbon particles have diameter in the range from0.125 mm to 0.297 mm. A particularly preferred activated carbon isactivated carbon wherein 85% or more of the activated carbon particleshave diameter in the range from 0.152 mm to 0.297 mm.

It is preferred that the activated carbon particles are formed bygrinding carbon material to the desired size. Ground activated carbonhas an irregular particle shape and this irregular shape may beparticularly suited to being cleanly delivered (e.g. from a deliverydevice, as described herein). The activated carbon may be in the form ofspheronised or spherical particles. The activated carbon may be coated.

The (pharmaceutical composition) may be delivered into a patient'srectal cavity, e.g. using a device. One suitable device comprises arectally-insertable cannula having a proximal opening, a distal opening,and a cavity defined through a body of the cannula between the proximalopening and the distal opening for containing the dose of pharmaceuticalcomposition. An openable closure acts to close the proximal opening ofthe canula. Preferably, the cannula is of length 6 to 8 cm, e.g 7 cm.For example, a one-way valve may act to close the proximal opening ofthe cannula, or alternatively a suitable closure means such as afrangible seal that ruptures on the application of pressure may be used.A frangible seal, or similar ruptureable closure, could only be used onetime, and would need to be replaced if the cannula is to be re-used. Thedevice further comprises an actuation means for driving a volume offluid (e.g. liquid such as water, or gas such as air) through theone-way valve (or alternative closure means) and the cavity to flush thedose of pharmaceutical composition out of the cavity through the distalopening of the cannula. The actuation means or actuator may comprise asuitable volume of liquid or may be loadable with a suitable volume ofliquid for flushing the cavity. For example, the actuation means oractuator may have a chamber for holding a volume of liquid that may befilled with a suitable liquid prior to use of the device. A suitableliquid should be a liquid that does not influence the adsorptivecapacity of the carbon and may be water or a medical solution, forexample a saline solution. The skilled person will be aware of suitableliquids that can safely be injected into a patient's rectum. In anotherexample, the actuation means or actuator may comprise a suitable volumeof gas (e.g air) or may be loadable with a suitable volume of gas (e.g.air).

By containing the pharmaceutical composition within the cavity of thecannula, the activated carbon can be maintained separately from theliquid (if the fluid is a liquid) until the point of delivery; in otherwords the pharmaceutical composition is a dry dose or dry powder. As theactivated carbon (the pharmaceutical composition) is stored in a drycondition it does not lose its activity for a considerable period oftime and, therefore, the activity of the carbon particles is high asthey are injected into the patient. Preferably, the driving liquid doesnot mix to a great extent with the activated carbon during delivery butmerely forces the activated carbon out of the distal opening of thecannula and into a patient's rectum. The function of the liquid is toact like a piston to drive the carbon into the patient, and the liquidmay therefore be referred to as a driving liquid or a propellant.

Preferably, the medicament consists of particles of activated carbonhaving an average particle size greater than 0.05 mm. For example, ifthe particle size is determined by sieving a portion of powder through agraded series of sieves, the average particles size determined in thisway is preferably greater than 0.05 mm. If the average particle size islower than 0.05 mm then the medicament may be difficult to handle, as itwill be prone to forming an airborne dust. Such fine particles aredifficult to wet and may also clump or agglomerate during storage and,therefore, may not flush from the cannula easily. The applicant'sexperiments indicate that if fine particles having average particle sizelower than 0.05 mm are used, 20% to 50% of the particles (i.e. the dose)may be retained in the syringe and therefore not actually administered.

The applicants have found that if the activated carbon is of particlesize 0.15 mm to 1 mm, it is preferred that the fluid (driving fluid) isa liquid (e.g. water). The applicants have surprisingly found that ifthe activated carbon is of particle size 0.05 mm to 0.15 mm, the fluid(driving fluid) may be a liquid (e.g. water) or a gas (e.g. air).

In addition to the preferred particle size ranges stated above, it ispreferred that the activated carbon has a bulk density or apparentdensity of from 0.015 to 0.6 g/cm³, for example from 0.4 g/cm³ to 0.5g/cm³, preferably from 0.44 g/cm³ to 0.45g/cm³. Bulk density may becalculated according to the standard procedure set out in ASTM D2854.The bulk density may be from 0.15 to 0.05 g/cm³.

The activated carbon particles are formed by grinding carbon material tothe desired size.

Loading the cannula with the pharmaceutical composition may be an actionundertaken by a patient. However, it may be convenient if the device ispreloaded with the pharmaceutical composition. The pharmaceuticalcomposition may, therefore, be loaded into the cannula cavity undercontrolled conditions and sealed at one end by the openable closure andat the other end by a sealing means. Such sealing means may, forexample, be a removable seal that is removed by the user before deliveryor a frangible seal that breaks on actuation. A suitable sealing meansmay be a cap or sheath that protects the external surface of thecannula, or at least of an insertable portion of the cannula. Thesealing means may even be a second one-way valve that allows passage ofthe contents of the cavity to pass out of the cannula when the device isactuated.

The actuation means may be a manually-operated actuator for example asyringe or a bellows or a bulb. The manually-operated actuator ispreferably capable of being filled with a driving liquid from a sourceof such liquid. For example, if the driving liquid is water then thewater may be supplied as sterile water for injection in a container,such as a flask or a vial, and then transferred to an actuation means,such as a syringe, prior to use of the device. It is preferable,therefore, that the actuation means is removably coupleable from thedevice to allow it to be filled or loaded with the driving liquid andthen coupled to the device in a suitable arrangement for forcing thedriving liquid through the one-way valve into the cannula cavity. It maybe advantageous for the actuation means to be an automatic actuator thatdelivers a volume of a driving liquid on, for example, the press of abutton. For example the actuation means may be a motorised actuator thatis operable to drive liquid from a source of liquid through the one-wayvalve and the cannula cavity to deliver the dose of particularpharmaceutical composition.

The device may comprise a flange or collar that extends radiallyoutwards from an external surface of the cannula at a predetermineddistance from the distal opening to determine the maximum depth ofinsertion of the cannula into the patient's rectum. Such a flange orcollar presents a physical barrier that prevents or hinders a portion ofthe cannula proximal to the flange or collar from easily being insertedthrough a patient's anus. The flange or collar may also help provide auser with purchase on the cannula to allow the application of insertionforce in the direction of a longitudinal axis of the cannula. Forexample, a user may apply a force on a proximal surface of a flange orcollar in order to insert the cannula to a depth at which a distalsurface of the flange or collar abuts the patient's anus.

The cannula may be preloaded with pharmaceutical composition in acontrolled environment. In such circumstances the loaded cannula may beconveniently supplied as a disposable component containing a preloadedvolume of pharmaceutical composition. Such a preloaded cannula could beattached to a device, the device could be activated to deliver thepharmaceutical composition, and then the spent cannula could be removedfrom the device and disposed of.

It may be convenient for a patient suffering from anal or rectal fistulato be supplied with a kit of parts for treatment of the diseasecomprising a device as described above. Thus, a further aspect of theinvention may provide a kit for the treatment of (e.g. anal and rectal)fistula comprising a delivery device (e.g. as described above); a supplyof activated carbon particles of particle size 0.001 to 1 mm, forexample 0.02 to 1 mm, preferably 0.05 to 1 mm (for example 0.1 to 0.5mm, for example 0.5 mm to 0.4 mm, for example 0.15 to 0.3 mm, forexample 0.2 to 0.3 mm); and optionally a source of fluid (e.g. liquid)for flushing the activated carbon particles through the device. Theactivated carbon may be of particle size 0.15 to 1 mm. The deliverydevice is preferably a device for rectal delivery of activated carbon.

Preferably the activated carbon is of average particle size 0.15 to 0.3mm. A still further aspect of the invention may provide a kit for thetreatment of (e.g. anal and rectal) fistula comprising a delivery device(e.g. as described above); a supply of activated carbon particleswherein 85% or more of the activated carbon particles have diameter inthe range from 0.089 mm to 0.3 mm (e.g. wherein 85% or more of theactivated carbon particles have diameter in the range from 0.152 mm to0.297 mm); and optionally a source of fluid (e.g. liquid) for flushingthe activated carbon particles through the device.

The fluid for flushing the activated carbon particles could be anysuitable liquid. Preferably the liquid is a liquid that does notinfluence the adsorptive properties of the activated carbon particlesand is safe for injection into a patient's rectum. The skilled personwill be aware of many such suitable liquids but as an example the liquidmay be sterile water, for example water for injection, a salt solution,etc. The fluid may be a gas (e.g. air).

As described above, it may be advantageous for the activated carbonparticles to be preloaded into disposable, rectally-insertable,cannulas. Thus, the invention may further provide a kit for thetreatment of anal and rectal fistula comprising a disposable,rectally-insertable, cannula including (e.g. a single dose of) activatedcarbon particles of particle size 0.001 to 1 mm, for example 0.02 to 1mm, preferably 0.05 to 1 mm [for example 0.1 to 0.5 mm, for example 0.5mm to 0.4 mm, for example 0.2 to 0.3 mm]; and optionally an activationmeans that can be filled or loaded with a volume of driving fluid (e.g.liquid). The activated carbon may be of particle size 0.15 to 1 mm.Preferably the activated carbon is of average particle size 0.15 to 0.3mm.

The invention may further provide a kit for the treatment of anal andrectal fistula comprising a disposable, rectally-insertable, cannulaincluding (e.g. a single dose of) activated carbon particles wherein 85%or more of the activated carbon particles have diameter in the rangefrom 0.089 mm to 0.3 mm (e.g. wherein 85% or more of the activatedcarbon particles have diameter in the range from 0.152mm to 0.297 mm);and optionally an activation means that can be filled or loaded with avolume of driving fluid (e.g. liquid or gas such as air).

The disposable cannula may be removably-coupleable to the activationmeans such that the activation means is capable of driving a volume ofthe fluid (e.g. liquid) through the openable closure of the cannula andthe cannula cavity to flush the dose of activated carbon out of thecannula cavity through the distal opening of the cannula. The kit mayalso comprise a supply of the driving liquid/fluid. Preferably, the kitcomprises a plurality of rectally-insertable cannulas, each cannulabeing removably-coupleable to the activation means and each cannulabeing loaded with a single dose of activated carbon. Preferably theactivated carbon is of average particle size 0.15 to 0.3 mm.

SPECIFIC EMBODIMENTS OF THE INVENTION

Specific embodiments of the invention will now be described withreference to the Figures in which:

FIG. 1 illustrates a device for delivering a dose of a pharmaceuticalcomposition for use in the treatment of fistula according to anembodiment of the invention comprising activated carbon particles;

FIG. 2 illustrates a rectally-insertable cannula for use as a componentpart of the device illustrated in FIG. 1;

FIG. 3 illustrates a longitudinal cross-section of therectally-insertable cannula of FIG. 2;

FIG. 4 illustrates a kit of parts for the treatment of rectal and analfistulas comprising a device according to the embodiment of FIG. 1 and asource of sterile water;

FIGS. 5 to 10 illustrate method steps involved in using the kit of FIG.4.

FIG. 1 illustrates a device 10 for delivering a dose of a pharmaceuticalcomposition comprising activated carbon particles into a patient'srectal cavity. The patient has been diagnosed with a rectal or analfistula by a medical professional (e.g. doctor) and has been assessed asbeing suitable for, and likely to be responsive to, such treatment. Thedevice comprises a rectally-insertable cannula 20, a syringe 30, and alength of flexible tubing 40 coupling the syringe 30 to the cannula 20.

The cannula 20 is illustrated in greater detail in FIGS. 2 and 3. Thecannula 20 has a generally elongated shape and has a proximal end 25 anda distal end 26. A cavity 22 is defined within a body 23 of the cannula20, the cavity having a proximal opening 21 at the proximal end of thecannula leading into the cavity 22 and a distal opening 24 at the distalend of the cannula leading out of the cavity 22. The cavity 22 extendslongitudinally between the proximal opening 21 and the distal opening24.

The body 23 of the cannula 20 further defines a radially-extendingflange or collar 27, which extends around a circumference of the cannulabody 23 between the proximal end 25 and the distal end 26. A portion ofthe cannula body extending from the radially-extending flange toward theproximal end of the cannula may be termed a proximal portion 25 a of thecannula body 23. Likewise, a portion of the cannula body 23 extendingfrom the radially-extending flange 27 to the distal end 26 may be termeda distal portion 26 a of the cannula.

In the specific embodiment described herein, the cannula is formed as atwo-piece construction. Thus, the distal portion of the cannula body 26a and the proximal portion of the cannula body 25 a are formed asseparate polyethylene components and then joined together to form thecannula 20. The radially-extending flange is formed as part of theproximal portion of the cannula 25 a, but could clearly be formed aspart of the distal portion of the cannula 26 a. The cannula may also beformed as a single component.

The distal portion 26 a of the cannula is externally-sized and shaped tobe inserted through a human anus into a human rectum in order to deliverthe pharmaceutical composition into the patient's rectal ampulla.Accordingly, the distal portion 26 a has a length of 7 cm and has asubstantially circular external cross-section. The distal portion 26 ais tapered at an angle of about 2° and has an outer diameter of 6.5 mmat the distal end 26. The radially-extending flange 27 has asubstantially circular cross-section and a diameter of 3.0 cm. Theproximal portion 25 a of the cannula body 23 is also of substantiallycircular cross-section and tapers from an inner diameter of about 7.7 mm(outer diameter 15.5 mm) adjacent to the radially-extending flange to aninner diameter of about 6.3 mm (outer diameter 8.7 mm) at the proximalend 25 of the cannula.

The cavity 22 defined within the cannula body 23 extends longitudinallythrough the cannula body from the proximal end 25 to the distal end 26.At the distal end 26 the cavity terminates at the distal opening 24. Thedistal opening is of substantially circular cross-section and has adiameter of 2.8 mm. At the proximal end of the cannula the cavity 22 isspanned by a one-way valve (not shown). The diameter of the cannula atthe proximal end is 6.3 mm. The one-way valve 50 is actuatable to allowfluids (e.g. liquids) to enter the cavity 22 through the proximalopening 21 of the cannula, but does not allow the passage of materialcontained within the cavity 22 of the cannula out of the cavity throughthe proximal opening 21. The cavity is about 120 mm in total length fromthe proximal opening to the distal opening. The cavity has a maximumdiameter in the region of the radially-extending flange, where theinternal cavity diameter is 7.7 mm. The volume of the cavity is about2.6 cm³, and the cannula is designed to be loaded with about 1.2 gram orabout 1.3 gram of activated carbon particles having a bulk density ofabout 0.45 g/cm³.

An upper surface 27 a of the radially-extending flange 27 acts as a stopto prevent the cannula from being inserted too far into a patient'srectum. As the cannula is inserted to its maximum penetration depth, theupper surface 27 a of the radially-extending flange abuts the patient'sanus and prevents inadvertent over-penetration. It is clear that theradially-extending flange does not need to extend around the entirecircumference of the cannula in order to perform this function. Anyradially-extending projection that hinders passage of the cannulathrough the anus may be used if over-penetration is a concern.

A lower surface 27 b of the radially-extending flange 27 a may act as alug that allows a user to apply an insertion-force in the direction ofthe distal end 26 of the cannula to facilitate its insertion.

The proximal end 25 of the cannula body 23 defines an internal cavity 28in which a threaded linkage is pressed so as to allow the cannula to becoupled to a source of driving fluid (e.g. liquid). The thread iscompatible with luer fittings as are well known in the medicalprofession. Luer fittings are commonly used to attach tubing andsyringes and needles for medical use.

The internal surface of the cavity 22 is substantially cylindrical incross-section and does not comprise any sudden changes in cross-sectionin order to minimise turbulence when a liquid is forced through thecavity 22.

In use, a pharmaceutical composition comprising activated carbonparticles is contained within the cavity 22.

The pharmaceutical composition comprises 1.2 g activated carbon ofaverage particle size 0.15 mm to 0.3 mm wherein 85% or more of theactivated carbon particles have diameter in the range from 0.152 mm to0.297 mm. The activated carbon is obtained from Chemviron Carbon testedto EUP 2010 Version 7.

The cavity 22 and the distal opening 24 are sized and shaped to optimisedelivery of activated carbon particles having an average particle sizeof between 0.15 mm and 0.3 mm. Particles of this size range are easierto handle compared with fine activated carbon particles previously usedfor medical treatments and do not stick or agglomerate within the cavityto a great extent, which would hinder their delivery. As the particlesare loaded within an elongated cavity that has a wide opening, the waterentering the cavity through the one-way valve effectively acts to pushthe particles out of this opening. Preferably the water does not mixwith the particles within the cavity (although some mixing isinevitable) but rather the front of the water entering through the valvepushes the cavity full of activated carbon particles ahead of it.

When loaded within the cavity 22, the activated carbon particles areprevented from escaping through the proximal opening 21 by means of theone-way valve 50 that spans the proximal opening. The distal opening 24may also be closed by a closure means in order to retain the particleswithin the cavity 22. For example, the device may comprise a removableseal or a frangible seal spanning the distal opening 24. Alternativelyor additionally, the device may comprise a cap that acts to close thedistal opening 24 and, thereby retain any pharmaceutical compositionwithin the cavity 22 until it is desired to use the device.

The cannula body is formed by an injection moulding process from amedical grade polyethylene. Polyethylene is a substantially inertmaterial that is commonly used in medical devices. It is noted that thecannula may be formed from any suitable medical material and that theperson skilled in the art would be aware of such material. For examplethe cannula may be made from a polyethylene, polupropylene or apolycarbonate or some other convenient medical grade polymer.

The syringe is a standard syringe having a liquid capacity of 12 ml, andcomprises a plunger 31 that is slidable within a barrel 32. The syringehas a threaded luer-type connection 33, which allows the syringe to becoupled to the flexible tubing 40. The syringe acts as an actuationmeans of the device for driving a volume of liquid through the cannulacavity 22 to flush a dose of pharmaceutical composition contained withinthe cannula cavity.

is The flexible tubing 40 is formed from a flexible medical-gradepolyvinyl chloride (PVC) and has an internal diameter of 2.6 mm, alength of 45 cm, and a capacity (i.e. the volume defined by the lumen ofthe tubing) of 2.4 ml. Each end of the flexible tubing terminates in aluer-type connection 41, 42. A first luer connection 41 allows theflexible tubing to be connected to the proximal end of the cannula 20while a second luer connection 42, at the opposite end of the flexibletubing to the first luer connection 41, allows the flexible tubing to beconnected to the syringe 30.

It may be particularly convenient to supply a patient with both thedevice and any further elements that they need to self-administer a doseof a pharmaceutical composition comprising activated carbon particles.Thus, it may be advantageous to supply component elements of a devicefor delivering a dose of pharmaceutical composition and other materialsin the form of a kit. An embodiment of such a kit is illustrated in FIG.4. This kit includes component parts of a device as described above,i.e. a rectally insertable cannula 20, a syringe 30, and a length offlexible tubing 40 for connecting the syringe to the cannula (theflexible tubing is shown connected to the cannula). The kit alsocomprises a container filled with water for injection 60. The water forinjection is used as a driving fluid to expel the pharmaceuticalcomposition through the cannula and into the patient.

The kit may comprise other components. For example, the kit may includea supply of activated carbon for loading into the cannula. The kit maycomprise a plurality of cannulas, each one pre-loaded with a dose ofactivated carbon.

In FIGS. 3 and 4, the cannula 20 is shown with its distal portion 26 asheathed within a cap 29. The cap comprises a stopper or bung 29 a and adownwardly depending sheath 29 b, and both sheaths the distal portion ofthe cannula 26 a and closes the distal opening 24 thereby retainingmedicament within the cannula.

The cannula is supplied pre-loaded with a pharmaceutical compositionconsisting of particles of activated carbon. The kit illustrated in FIG.4 may be used to deliver a dose of a pharmaceutical compositioncomprising activated carbon particles as described below.

FIGS. 5 to 10 illustrate a method of using the kit as illustrated inFIG. 4 in order to deliver a dose of activated carbon particles into apatient's rectal cavity. The individual component parts of the kit areremoved from packaging in which they are supplied and set out before theuser. The plunger 31 of the syringe 30 is withdrawn to the 11 ml markingon the barrel 32 of the syringe (as illustrated in FIG. 5). The userthen removes a sealing cork 61 that acts to seal the container of waterfor injection 60 (illustrated in FIG. 6). The container of water 60 ismaintained in an upright position so that its contents are not spilled.

The syringe 30 is coupled to the water container 60 in order to chargethe syringe with water. The threaded luer connection 33 of the syringeengages with a corresponding mating thread in the neck 62 of the watercontainer 60 (illustrated in FIG. 7).

The water container 60, with the syringe now affixed, is inverted(illustrated in FIG. 8). The plunger 31 of the syringe 30 is thendepressed to the 3 mm mark. This action causes air within the barrel ofthe syringe to be forced into the water container 60, which pressurisesthe container. The plunger is then withdrawn again. On withdrawal of theplunger, the water for injection passes into the barrel of the syringe.If required, the plunger can be repeatedly depressed and withdrawn.After these steps the barrel of the syringe should be filled with waterfor injection from the container of water 60 (this is illustrated inFIG. 9). Clearly, any technique for filling the syringe with the watermay be used.

The cannula 20, which is preloaded with the pharmaceutical compositionas described above, is coupled to the flexible tubing by screwing in theluer connections on the flexible tubing with equivalent connections onthe cannula. Likewise, the flexible tubing is also connected to thesyringe filled with water by coupling the luer connections on theflexible tubing and on the syringe (FIG. 10).

Immediately prior to use the cover or cap 29 is removed from the cannula20. This opens the distal opening 24 such that the pharmaceuticalcomposition can be forced out. If desired, the external surfaces of thedistal portion 26 a of the cannula may be lubricated, for example withpetroleum jelly. Such lubrication may improve a patient's comfort oninserting the cannula. In some embodiments the distal portion of thecannula may be pre-lubricated. The distal portion 26 a of the cannula 20is then inserted carefully through the patient's anus so that the distalend 26 and the distal opening 24 enter the patient's rectal cavity. Thecannula should be inserted until the radially-extending flange 27 abutsthe anus and prevents further insertion.

With the cannula in place, the plunger 31 of the syringe 30 is pressedquickly. The plunger should preferably travel to its full extent over aperiod of no longer than 2 seconds. The water for injection containedwithin the barrel of the syringe is forced out of the syringe andthrough the flexible tubing 40, through the one-way valve 50 that closesthe proximal opening 21 of the cannula and into the cannula cavity. Onentering the cannula cavity 22, the flow of water forces thepharmaceutical composition that is contained within the cavity out ofthe cavity through the distal opening 24 and into the patient's rectalcavity.

After delivery of the pharmaceutical composition the cannula is removedfrom the patient's rectum. The cannula may then be cleaned, if it is tobe re-used, or disposed of, if the device is only intended forone-time-use.

The device, kit, and method of using the device and kit as describedherein refer to a specific embodiment. It is clear that many factors maybe varied without changing the nature of the invention. For example, theembodiment described in detail above utilises a syringe as an actuationmeans for driving a volume of liquid through the cannula cavity. Anysuitable actuation means may be used instead. For example, it may bepossible to use a bellows or a bulb as an alternative to a syringe. Inparticular, it may be possible to replace the syringe with an automaticor motorised injection means for driving the volume of liquid.

The actual volume of liquid injected, and therefore the size of thesyringe, may be varied. For example, such variation may be desirable ifthe volume of the cannula cavity is larger or smaller than theembodiment described above, or if the length of flexible tubing islonger or shorter. The volume of liquid should be sufficient to drivethe entire contents of the cannula into the patient's rectum withoutdelivering an excessive volume of liquid to the patient.

Although the embodiment described above uses flexible tubing disposedbetween the syringe and the cannula, other embodiments may dispense withthe flexible tubing and provide a direct connection between the cannulaand syringe or other means for driving the volume of liquid.

The size and shape of the cannula may be varied from the dimensionsdescribed in the embodiment above. Different sized cannulas may, forexample, allow different volumes of pharmaceutical composition to bedispensed to a patient.

As set out above, the applicants have found that if the activated carbonis of particle size 0.15 mm to 1 mm, a liquid (e.g. water) should beused as driving fluid to deliver the dry powder. The applicants havesurprisingly found that if the activated carbon is of particle size 0.05mm to 0.15 mm, the fluid (driving fluid) may be either a liquid (e.g.water, as above) or a gas (e.g. air).

EXAMPLE 1 An Open Prospective Study Evaluating the Efficacy and Safetyof Activated Carbon for the Treatment of Chronic, Non-complicatedPerianal Fistulas

Background

The activated carbon was administered using the device described aboveand illustrated in the attached Figures.

Spontaneous fistula healing rates are considered to be very low, of theorder of 4 to 5% (clinical experience of the participatinginvestigators). For saftey, a value of 10% was used in setting up thetrial (e.g. for the subject number calculation) meaning that anuncontrolled design could be selected as the preferred design for thisinitial pilot trial. This design allows for a preliminary indication ofeffect.

Clinical assessment of fistula healing (healed/not healed), was selectedas the primary endpoint since this is the endpoint used in dailyclinical practice. Rectal ultrasound evaluations were also made becausethese can provide more detailed measures of the degree of healing ascompared to the clinical evaluation (healed/not healed).

The secondary endpoints are less established, but still of importance tothe evaluation of benefit/effect. It is very important to measure if thepatient feels any improvement but there are no validated tools availableto measure patient reported outcome in perianal fistulising disease. Inthis study, a VAS scale was used to assess pain and soiling, and aquestionnaire was used to evaluate the impact on daily function, andalso perception of ease of use.

Dose and Timing

The dose administered by the medical device in the trial was 2.6 g/day.In order to provide as much activated carbon to the affected areas aspossible the device was used twice daily (with at least 6 hours inbetween administrations); thus, the device was used to administeractivated carbon at a dose of 1.3 g twice daily.

The dose was administered by the patient in the morning: after breakfast(after defecation), and in the evening, prior to “going to bed”.

A treatment period of 8 weeks was chosen. Since the main problem withall existing treatment modalities is the high recurrence rates (20-60%),it is relevant to perform a follow up visit. In this study the follow-upvisit was scheduled to be performed at least 4 months after the lastadministration.

Selection of the Trial Population

For this initial trial in perianal fistulas a population with fewcomplications and low, more easily accessible, location was selected.Thirty patients were selected. The recruitment of patients was performedas described below:

-   1. Patients who have symptoms from their fistulas and were referred    or contacted the site themself were offered an opportunity to    participate in the trial.-   2. Following review of patient records/data bases patients were    contacted and asked to participate in the trial.

The inclusion criteria for the trial are as follows:

-   1. Patients with perianal fistulas diagnosed by clinical examination    and evaluated as “not healed/open”-   2. Fistula classified as intersphincteric and transsphincteric    according to Parks'classification 3. Superficial fistula involving a    part of the external sphincter muscle-   4. Age: ≧18 years and ≦75 years-   5. Informed consent and/or Letter of Authority (as applicable)    obtained

The exclusion criteria were as follows:

-   6. Inflammatory Bowel Disease (IBD)-   7. Rectovaginal fistulas-   8. Rectouretral fistulas-   9. Rectovescical fistulas-   10. Extra-sphincteric and supra-sphincteric fistula according to    Parks'classification-   11. Complicated fistulas (eg. horse shoe fistulas) as evaluated by    the investigator.-   12. Any previous surgical treatment for perianal fistulas-   13. Subcutaneous fistulas not involving any part of the external    sphincter-   14. Colorectal and/or anal malignancy-   15. Other malignancy requiring active treatment-   16. Other diseases which as per the investigator's opinion should be    contraindicated

17. Subjects who are not able to complete study procedures as per theinvestigator's opinion

There are no restrictions in the therapy received prior to this trial.Anti inflammatory therapies (as NSAIDs), antibiotics or immunomodulatoryconcomitant therapies (including corticosteroids, metronidazole and antiTNFα therapy) were not allowed during the trial. Any other therapy forthe fistula was avoided during participation in the trial.

The Investigational Medical Device (IMD) is illustrated in the theattached drawings (see especially FIGS. 1 and 4) and consisted of:

-   1. Rectal cannula set-   a. Rectal cannula with cap, valve and carbon chamber-   b. Connection tube with female connector-   c. Vaseline plug (soft yellow paraffin/vaselinum flavum)-   d. Activated carbon 1.3 g (for injection into the rectum)-   2. Sterile water (Ph. Eur. Quality) 10 ml in plastic container-   3. Sterile syringe (CE-marked)—10 ml

All medical devices are provided by Nordic Drugs AB. Subjects weretrained in the use of the device by the investigator or a nurse. Theactivated carbon (Activated Carbon 610C (EUP 2010) was administeredusing 10 ml. sterile water (Fresenius Kabi) by means of a sterilesyringe (BRAUN lnjekt, CE marked), by the method described above.

All medicinal device components were handled according to the principlesof Good Manufacturing Practice and applicable ISO guidelines.

Trial Procedure

Day 1/Baseline

On day 1, consent was obtained and the patient instructed in how to usethe device. The investigator performed an overall assessment of thepatients state of health in order to confirm eligibility. Except fordigital rectal examination and the clinical evaluation of the fistula noexaminations are required. A rectoscopy was performed in order to ruleout malignancies and high located fistulas. Samples were taken and sentto the local laboratory to be ananlysed for: CRP, Hb and WBC.

A clinical evaluation of fistula anatomy was made by analultrasonography.

The Form for Patient Assessment of Symptoms and Impact on Daily Functionwas handed out to patient and completed at the visit.

Week 2 (Telephone Visit):

By telephone interview the patients were asked if they had used theMedical Device; patients are asked if they have experienced any problemswith the device and if they have observed any adverse events.

Week 8 (End of Intervention)

The investigator performed an overall assessment of the patients stateof health in order to observe any possible changes (=Adverse events) notalready reported by the patient. Except for digital rectal examinationand the clinical evaluation of the fistula no examinations wereperformed.

Patients were asked if they have experienced any problems with thedevice and if they have observed any adverse events.

A rectoscopy was performed. Samples were taken and sent to the locallaboratory to be ananlysed for: CRP, Hb and WBC.

A clinical evaluation of fistula closure was made by analultrasonography (for fistula healing and type). The Form for PatientAssessment of Symptoms and Impact on Daily Function was handed out topatient and completed at the visit. Medical Device patientacceptability/performance questions were asked.

Week 24 (Follow-up)

A medical examination was made (digital rectal examination only),together with clinical evaluation of fistula closure by analultrasonography (fistula healing and type). The Form for PatientAssessment of Symptoms and Impact on Daily Function is handed out topatient and again completed at the visit.

Assessments and Results

The primary endpoint was clinical assessment of fistula healing(healed/not healed). Healing was defined as the fistula closed and nosecretion as observed by visual inspection.

A rectoscopy was performed, and the result given on a scale of 1 to 5(1=ulcerations, 2=fistula, 3=Abscess, 4=Stenosis, 5=fissure).

A Form for Patient Assessment of Symptoms and Impact on Daily Functionwas handed out to the patients. A 10 point VAS scale was be used toassess pain and soiling (0=no pain/soiling, 10=unbearable pain/soiling).In additions a questionnaire was used to assess the impact on dailyfunction. The patients were also asked the following questions relatingto the Medical Device at study end:

-   1 Would you like to use KULIST again?

If the answer is no: please explain why

-   2 Describe advantages and disadvantages of the device-   3 Have you had any difficulties in using the device-   4 Could the device be more user friendly? How?    Results

The following preliminary results are based on week 8 (end ofintervention) data from 26 of the 28 enrolled patients.

Data on the primary endpoint, healing, indicates that over 30% (30.7%)have complete healing (fistula closed, no discharge). The confidenceinterval (data not shown) indicates the results are of statisticalsignificance. This is a spectacular improvement on the spontaneoushealing rate assessed by the clinic (4 to 5%), and is indicative thatthis treatment may provide a real alternative to surgery.

Oral communcation with the test sites have reveiled that at least 2other patients have, in addition experienced, improvements and signs ofhealing such as reduced soiling.

The patients generally found the rectal system to be easy to operate.

The only adverse event observed (1 patient) was constipation. There wereno side effects or adverse events from the device itself reported. Thus,the use of rectally administered activated carbon (of specific size) iseffective and avoids the drawbacks of previous methods, and the risksassociated with surgical intervention.

EXAMPLE 2

The activated carbon was administered using the device described aboveand illustrated in the attached Figures.

Activated carbon of particle size 0.05 to 0.15 mm (mesh size 100×270 USmesh) was administered using air (instead of water) as thepropellant/fluid. The applicants found that administration waseffectively administered rectally, with air as the propellant. Theapplicants also found that activated carbon of particle size 0.05 to0.15 mm (mesh size 100×270 US mesh) was effectively administered usingwater as the propellant/fluid.

The invention claimed is:
 1. A method for the treatment of fistula, themethod comprising administering to a subject in need of such treatment apharmaceutically effective amount of a composition consisting ofparticles of activated carbon, wherein the activated carbon isadministered rectally as a dry dose, and wherein the activated carbon isdriven into the rectum of the subject using a driving fluid.
 2. A methodaccording to claim 1, wherein the activated carbon is of averageparticle size 0.05 mm to 1 mm.
 3. A method according to claim 1, whereinthe activated carbon is of average particle size 0.15 mm to 1 mm.
 4. Amethod for the treatment of fistula, the method comprising administeringto a subject in need of such treatment a pharmaceutically effectiveamount of a composition consisting of particles of activated carbonwherein 85% or more of the activated carbon particles have diameter inthe range from 0.089 mm to 0.3 mm, wherein the activated carbon isadministered rectally as a dry dose, and wherein the activated carbon isdriven into the rectum of the subject using a driving fluid.
 5. A methodaccording to claim 4, wherein 85% or more of the activated carbonparticles have diameter in the range from 0.152 mm to 0.297 mm.
 6. Amethod according to claim 1, wherein the fistula is rectal fistula.
 7. Amethod according to claim 1, wherein the amount of activated carbonadministered is in the range from 450 μg to 10 g.
 8. A method accordingto claim 1, wherein the activated carbon is granular.
 9. A methodaccording to claim 1, wherein 90% or more of the activated carbonparticles have diameter in the range from 0.125 mm to 0.297 mm.
 10. Amethod according to claim 1, wherein 85% or more of the activated carbonparticles have diameter in the range from 0.152 mm to 0.297 mm.
 11. Amethod for the treatment of fistula, the method comprising administeringto a subject in need of such treatment a composition consisting of a drypowder of activated carbon which is dust free, wherein the compositionis administered rectally as a dry dose, and wherein the activated carbonis driven into the rectum of the subject using a driving fluid.
 12. Amethod for the treatment of fistula, the method comprising administeringto a subject in need of such treatment a composition consisting of a drypowder (a dry dose) of activated carbon of particle size 0.001 to 1 mm,wherein the composition is administered rectally, and wherein theactivated carbon is driven into the rectum of the subject using adriving fluid.
 13. A method according to claim 1, wherein the activatedcarbon is of average particle size 0.02 to 1 mm.
 14. A method accordingto claim 1, wherein the activated carbon is of average particle size0.15 mm to 0.3 mm.
 15. A method according to claim 1, wherein thefistula is anal fistula.
 16. A method according to claim 1, wherein theactivated carbon is ground activated carbon having an irregular particleshape.
 17. A method according to claim 1, wherein the composition isadministered using a disposable, rectally-insertable, cannula containingthe composition.
 18. The method of claim 1, wherein the driving fluid isa liquid.
 19. The method of claim 18, wherein the driving fluid iswater.
 20. The method of claim 1, wherein the driving fluid is a gas.21. The method of claim 20, wherein the driving fluid is air.
 22. Themethod of claim 18, wherein the activated carbon is of particle size0.15 mm to 1 mm.
 23. The method of claim 19, wherein the activatedcarbon is of particle size 0.15 mm to 1 mm.
 24. The method of claim 18,wherein the activated carbon is of particle size 0.05 mm to 0.15 mm. 25.The method of claim 19, wherein the activated carbon is of particle size0.05 mm to 0.15 mm.
 26. The method of claim 20, wherein the activatedcarbon is of particle size 0.05 mm to 0.15 mm.
 27. The method of claim21, wherein the activated carbon is of particle size 0.05 mm to 0.15 mm.28. The method of claim 1, wherein the treatment comprises closing thefistula.
 29. The method of claim 1, wherein the treatment compriseshealing the fistula, wherein the healing comprises closing the fistulawithout discharge.
 30. The method of claim 1, wherein the activatedcarbon is administered twice daily.
 31. The method of claim 30, whereinthe activated carbon is administered once in the morning and once in theevening.
 32. The method of claim 30, wherein the treatment comprisesclosing the fistula within eight weeks of commencing treatment.
 33. Themethod of claim 1, wherein the driving fluid is maintained separatelyfrom the driving fluid until immediately before the activated carbon isadministered.
 34. A method for the treatment of fistula in a subject inneed thereof, the method comprising providing a device containing aformulation that consists of particles of activated carbon as a drydose, and further contains the driving fluid maintained separately fromthe activated carbon; inserting the device into the rectum of thesubject; and actuating the device to cause the activated carbon to bedriven into the rectum of the subject by the driving fluid.
 35. Themethod of claim 34, wherein the activated carbon is of particle size0.15 mm to 1 mm and the driving fluid is a liquid; or wherein theactivated carbon is of particle size 0.05 mm to 0.15 mm and the drivingfluid is a liquid or a gas.
 36. The method of claim 35, wherein thedriving fluid is a liquid.
 37. The method of claim 36, wherein thedriving fluid is water.
 38. The method of claim 35, wherein the drivingfluid is a gas.
 39. The method of claim 38, wherein the driving fluid isair.
 40. The method of claim 1, wherein the treatment is continued for aperiod of at least 8 weeks.
 41. The method of claim 40, wherein theactivated carbon is administered twice daily during the treatmentperiod.